KAT2A upregulates the Tfrc/Hmox1-mediated ferroptosis pathway to disrupt neovascular structure and impair healing function in Fibroblasts under high-glucose conditions

Background Diabetic foot ulcer (DFUs) is a serious complication related to diabetes, which is caused by long-term inflammation, increased blood sugar levels and wound healing disorders caused by fibroblast dysfunction. The dysfunction of fibroblasts in DFU wounds, especially the loss of function to mediate the construction of neovascular networks, is considered to be the key to the failure of DFU healing. In-depth exploration of the molecular mechanism of fibroblast dysfunction in a high-sugar environment is very important for the treatment of DFU. Methods We integrate both single-cell and bulk transcriptomic data for bioinformatics and machine learning analyses; functional validation was performed in HFF-1 fibroblasts exposed to high-glucose conditions, with KAT2A gain- and loss-of-function experiments and DFO treatment used to assess ferroptosis-related changes. Results Single-cell analysis revealed a significant rise in a specific subgroup of fibroblasts exhibiting high levels of KAT2A expression within DFUs. This increase showed a positive relationship with genes linked to ferroptosis and an inverse relationship with those associated with angiogenesis. Cell communication assays showed impaired pro-angiogenic fibroblast-endothelial signaling in DFUs. Elevated glucose concentrations caused a dose-dependent increase in KAT2A levels, inducing ferroptosis, which was characterized by the accumulation of Fe 2+ , depletion of glutathione (GSH), heightened malondialdehyde (MDA) levels, and decreased expression of Glutathione peroxidase 4 (GPX4) and Solute carrier family 7 member 11 (SLC7A11). The enhanced expression of KAT2A exacerbated the ferroptosis phenotype and led to increased levels of Tfrc and Hmox1, while DFO treatment partially alleviated these effects. Conclusion The study suggests that the KAT2A–Tfrc/Hmox1–ferroptosis pathway may play an important role in diabetic fibroblast dysfunction and impaired wound repair. This mechanism leads to ferroptosis and impaired angiogenesis, which ultimately hinders the healing process of DFUs. This finding provides new avenues for targeted therapies centered on KAT2A and iron chelation.